David Wotton

Education

  • BS, University of York, England
  • PhD, Imperial Cancer Research Fund, London

Primary Appointment

  • Associate Professor, Biochemistry and Molecular Genetics

Contact

Research Interest(s)

Regulation of Gene Expression and Development by Transcriptional Repressors

Research Description

Our main area of study is the regulation of gene expression by transcriptional repressors. We are particularly interested in how transcriptional corepressors control mammalian development and regulate cell cycle progression. We focus on two related corepressor proteins called Tgif1 and Tgif2. The major way in which Tgifs regulate gene expression is through recruitment to DNA via other DNA bound transcription factors. Once recruited to DNA Tgifs will inhibit gene expression, and their function appears to be to limit transcriptional activation in response to specific signaling pathways. Activation of gene expression by transforming growth factor beta (TGFß) is the best studied target of the Tgifs. The gene responses activated by TGFß family signaling underlie many developmental and proliferative responses in mammalian cells. For example, perturbation of TGFß signaling due to mutations in components of the signal transduction pathway contributes to numerous human cancers. In response to TGFß signaling, Smad transcription factors accumulate in the nucleus, where they activate target gene expression. Tgifs compete with transcriptional coactivators for Smad interaction, and recruit corepressors to limit the activation of TGFß/Smad target genes. Our recent work has demonstrated that Tgif1 can also be recruited to DNA indirectly via interaction with the RXR nuclear receptor. RXR is a partner for many other nuclear receptors, including retinoic acid receptors, and Tgif1 represses a subset of nuclear receptor targets, including genes which are responsive to retinoic acid. We are currently examining the role of Tgif1 in other RXR-dependent nuclear receptor signaling pathways. At present, we are continuing to analyze the mechanism by which Tgifs function, using standard biochemical approaches. We are also attempting to identify, more globally, which genes are regulated by Tgifs using expression microarray technology, and testing recruitment of Tgifs, and associated corepressors, to target genes. In humans, heterozygous mutations in TGIF result in holoprosencephaly, a prevalent genetic disorder affecting craniofacial development. To examine the in vivo functions of Tgifs, we have created mouse knock-outs of both Tgif and Tgif2. Complete loss of both Tgifs results in gastrulation defects and embryonic lethality, and we are trying to understand how Tgifs regulate early embryonic development. In addition, we are using conditional mutations to study Tgif function later during embryogenesis, and to determine how mutation of Tgifs causes holoprosencephaly.

Selected Publications

  • Bjerke G, Pietrzak K, Melhuish T, Frierson H, Paschal B, Wotton D. Prostate cancer induced by loss of Apc is restrained by TGFβ signaling. PloS one. 2014;9(3): e92800. PMID: 24651496 | PMCID: PMC3961420
  • Pramfalk C, Melhuish T, Wotton D, Jiang Z, Eriksson M, Parini P. TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2. Journal of lipid research. 2014;55(4): 709-17. PMID: 24478032 | PMCID: PMC3966704
  • Bjerke G, Yang C, Frierson H, Paschal B, Wotton D. Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. Oncogene. 2013. PMID: 23995785 | PMCID: PMC3939071
  • Yan L, Womack B, Wotton D, Guo Y, Shyr Y, Davé U, Li C, Hiebert S, Brandt S, Hamid R. Tgif1 regulates quiescence and self-renewal of hematopoietic stem cells. Molecular and cellular biology. 2013;33(24): 4824-33. PMID: 24100014 | PMCID: PMC3889555
  • TGF-β drives DNA demethylation. Molecular cell. 2012;46(5): 556-7. PMID: 22681884
  • Taniguchi K, Anderson A, Sutherland A, Wotton D. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS genetics. 2012;8(2): e1002524. PMID: 22383895 | PMCID: PMC3285584
  • Zerlanko B, Bartholin L, Melhuish T, Wotton D. Premature senescence and increased TGFβ signaling in the absence of Tgif1. PloS one. 2012;7(4): e35460. PMID: 22514746 | PMCID: PMC3325954
  • Bjerke G, Hyman-Walsh C, Wotton D. Cooperative transcriptional activation by Klf4, Meis2, and Pbx1. Molecular and cellular biology. 2011;31(18): 3723-33. PMID: 21746878 | PMCID: PMC3165729
  • Hyman-Walsh C, Bjerke G, Wotton D. An autoinhibitory effect of the homothorax domain of Meis2. The FEBS journal. 2010;277(12): 2584-97. PMID: 20553494
  • Melhuish T, Chung D, Bjerke G, Wotton D. Tgif1 represses apolipoprotein gene expression in liver. Journal of cellular biochemistry. 2010;111(2): 380-90. PMID: 20506222 | PMCID: PMC2939915
  • Merrill J, Kagey M, Melhuish T, Powers S, Zerlanko B, Wotton D. Inhibition of CtBP1 activity by Akt-mediated phosphorylation. Journal of molecular biology. 2010;398(5): 657-71. PMID: 20361981 | PMCID: PMC2866129
  • Merrill J, Melhuish T, Kagey M, Yang S, Sharrocks A, Wotton D. A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity. PloS one. 2010;5(1): e8794. PMID: 20098713 | PMCID: PMC2808386
  • Quijano J, Stinchfield M, Zerlanko B, Gibbens Y, Takaesu N, Hyman-Walsh C, Wotton D, Newfeld S. The Sno oncogene antagonizes Wingless signaling during wing development in Drosophila. PloS one. 2010;5(7): e11619. PMID: 20661280 | PMCID: PMC2905394
  • Vincent D, Kaniewski B, Powers S, Havenar-Daughton C, Marie J, Wotton D, Bartholin L. A rapid strategy to detect the recombined allele in LSL-TβRICA transgenic mice. Genesis (New York, N.Y. : 2000). 2010;48(9): 559-62. PMID: 20645310 | PMCID: PMC2944915
  • Powers S, Taniguchi K, Yen W, Melhuish T, Shen J, Walsh C, Sutherland A, Wotton D. Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation. Development (Cambridge, England). 2009;137(2): 249-59. PMID: 20040491 | PMCID: PMC2799159
  • Bartholin L, Melhuish T, Powers S, Goddard-Léon S, Treilleux I, Sutherland A, Wotton D. Maternal Tgif is required for vascularization of the embryonic placenta. Developmental biology. 2008;319(2): 285-97. PMID: 18508043 | PMCID: PMC2517231
  • Chung D, Honda K, Cafuir L, McDuffie M, Wotton D. The Runx3 distal transcript encodes an additional transcriptional activation domain. The FEBS journal. 2007;274(13): 3429-39. PMID: 17555522
  • Wotton D, Merrill J. Pc2 and SUMOylation. Biochemical Society transactions. 2007;35 1401-4. PMID: 18031231
  • Bartholin L, Powers S, Melhuish T, Lasse S, Weinstein M, Wotton D. TGIF inhibits retinoid signaling. Molecular and cellular biology. 2006;26(3): 990-1001. PMID: 16428452 | PMCID: PMC1347013
  • El-Jaick K, Powers S, Bartholin L, Myers K, Hahn J, Orioli I, Ouspenskaia M, Lacbawan F, Roessler E, Wotton D, Muenke M. Functional analysis of mutations in TGIF associated with holoprosencephaly. Molecular genetics and metabolism. 2006;90(1): 97-111. PMID: 16962354 | PMCID: PMC1820763
  • Melhuish T, Wotton D. The Tgif2 gene contains a retained intron within the coding sequence. BMC molecular biology. 2006;7 2. PMID: 16436215 | PMCID: PMC1402312
  • Takaesu N, Hyman-Walsh C, Ye Y, Wisotzkey R, Stinchfield M, O'connor M, Wotton D, Newfeld S. dSno facilitates baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2. Genetics. 2006;174(3): 1299-313. PMID: 16951053 | PMCID: PMC1667060
  • Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes & development. 2005;19(23): 2783-810. PMID: 16322555
  • Kagey M, Melhuish T, Powers S, Wotton D. Multiple activities contribute to Pc2 E3 function. The EMBO journal. 2004;24(1): 108-19. PMID: 15592428 | PMCID: PMC544918
  • Hyman C, Bartholin L, Newfeld S, Wotton D. Drosophila TGIF proteins are transcriptional activators. Molecular and cellular biology. 2003;23(24): 9262-74. PMID: 14645536 | PMCID: PMC309625
  • Kagey M, Melhuish T, Wotton D. The polycomb protein Pc2 is a SUMO E3. Cell. 2003;113(1): 127-37. PMID: 12679040
  • Lo R, Wotton D, Massagué J. Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF. The EMBO journal. 2001;20(1): 128-36. PMID: 11226163 | PMCID: PMC140192
  • Melhuish T, Gallo C, Wotton D. TGIF2 interacts with histone deacetylase 1 and represses transcription. The Journal of biological chemistry. 2001;276(34): 32109-14. PMID: 11427533
  • Wotton D, Knoepfler P, Laherty C, Eisenman R, Massagué J. The Smad transcriptional corepressor TGIF recruits mSin3. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 2001;12(9): 457-63. PMID: 11571228
  • Wotton D, Massagué J. Smad transcriptional corepressors in TGF beta family signaling. Current topics in microbiology and immunology. 2001;254 145-64. PMID: 11190572
  • Gripp K, Wotton D, Edwards M, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai E, Massagué J, Muenke M, Elledge S. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nature genetics. 2000;25(2): 205-8. PMID: 10835638
  • Massagué J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. The EMBO journal. 2000;19(8): 1745-54. PMID: 10775259 | PMCID: PMC302010
  • Melhuish T, Wotton D. The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. The Journal of biological chemistry. 2000;275(50): 39762-6. PMID: 10995736